tbuckley/cabot-search huggingface dataset:
Small Molecule Inhibitors of IκB Kinase Are Selectively Toxic for Subgroups of Diffuse Large B-Cell Lymphoma Defined by Gene Expression Profiling
Authors: Lloyd T. Lam, R. Eric Davis, Jackie Pierce, Michael Hepperle, Yajun Xu, Maria Hottelet, Yuhua Nong, Danyi Wen, Julian Adams, Lenny Dang, Louis M. Staudt
Journal: Clinical Cancer Research (2005)

Abstract Constitutive activation of the NF-κB pathway is required for survival of the activated B cell–like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IκB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell–like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-κB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-κB was created by fusing the p65 NF-κB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-κB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-κB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-κB target genes. These studies validate the NF-κB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-κB for survival and proliferation.
National Standards for Diabetes Self-Management Education
Authors: Martha M. Funnell, Tammy L. Brown, Belinda P. Childs, Linda B. Haas, Gwen M. Hosey, Brian Jensen, Melinda Maryniuk, Mark Peyrot, John D. Piette, Diane Reader, Linda M. Siminerio, Katie Weinger, Michael A. Weiss
Journal: Diabetes Care (2010)
Nanomedicine and versatile therapies for cancer treatment
Authors: Aparna Shukla, Pralay Maiti
Journal: MedComm (2022)

The higher prevalence of cancer is related to high rates of mortality and morbidity worldwide. By virtue of the properties of matter at the nanoscale, nanomedicine is proven to be a powerful tool to develop innovative drug carriers with greater efficacies and fewer side effects than conventional therapies. In this review, different nanocarriers for controlled drug release and their routes of administration have been discussed in detail, especially for cancer treatment. Special emphasis has been given on the design of drug delivery vehicles for sustained release and specific application methods for targeted delivery to the affected areas. Different polymeric vehicles designed for the delivery of chemotherapeutics have been discussed, including graft copolymers, liposomes, hydrogels, dendrimers, micelles, and nanoparticles. Furthermore, the effect of dimensional properties on chemotherapy is vividly described. Another integral section of the review focuses on the modes of administration of nanomedicines and emerging therapies, such as photothermal, photodynamic, immunotherapy, chemodynamic, and gas therapy, for cancer treatment. The properties, therapeutic value, advantages, and limitations of these nanomedicines are highlighted, with a focus on their increased performance versus conventional molecular anticancer therapies.
Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT)
Authors: Michal Grzmil, Paul Boersema, Ashish Sharma, Alain Blanc, Stefan Imobersteg, Martin Pruschy, Paola Picotti, Roger Schibli, Martin Behe
Journal: Journal of Hematology & Oncology (2022)

The vast majority of our knowledge regarding cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam radiation therapy (EBRT). Yet, less is known about the cancer response to internal targeted radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled minigastrin analogue [177Lu]Lu-PP-F11N (β-emitter) and EBRT (ɣ-rays) in CCKBR-positive cancer cells. Activation of DNA damage response by p53 was induced by both types of radiotherapy, whereas TRT robustly increased activation of signaling pathways including epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs) or integrin receptor. Inhibition of EGFR or integrin signaling sensitized cancer cells to radiolabeled minigastrin. In vivo, EGFR inhibitor erlotinib increased therapeutic response to [177Lu]Lu-PP-F11N and median survival of A431/CCKBR-tumor bearing nude mice. In summary, our study explores a complex scenario of cancer responses to different types of irradiation and pinpoints the radiosensitizing strategy, based on the targeting survival pathways, which are activated by TRT.
Incidence of in Situ vs Invasive Melanoma: Testing the “Obligate Precursor” Hypothesis
Authors: Catherine M Olsen, Nirmala Pandeya, Philip S Rosenberg, David C Whiteman
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Melanoma incidence has been rising in populations with predominantly European ancestry (White), speculated to be partly driven by heightened detection of indolent tumors. If in situ melanomas are destined to evolve to invasive cancers, detecting and removing them should deplete the pool of invasive lesions, and people with in situ melanoma should, on average, be younger than those with invasive melanoma. Methods We analyzed long-term incidence trends (1982-2018) for in situ and invasive melanomas in 3 predominantly White populations with high, medium, and low melanoma rates: Queensland (Australia), United States White, and Scotland. We calculated the incidence rate ratio (IRR) of in situ to invasive melanomas and estimated the contributions of age, period, and cohort effects. We compared age at diagnosis of in situ vs invasive melanomas overall and stratified by sex and anatomic site. Results In all 3 populations, the in situ to invasive incidence rate ratio increased statistically significantly from less than 0.3 in 1982 to 1.95 (95% confidence interval [CI] = 1.88 to 2.02) in Queensland, 0.93 (95% CI = 0.90 to 0.96) in the US White population, and 0.58 (95% CI = 0.54 to 0.63) in Scotland in 2018. The mean age at diagnosis of in situ melanomas was the same or higher than invasive melanomas for almost all time periods among men and women and on all body sites except the lower limbs. Conclusions The increasing ratio of in situ to invasive melanoma incidence over time, together with the high (and increasing) mean age at diagnosis of in situ melanomas, is consistent with more indolent lesions coming to clinical attention than in previous eras.
Postgraduate medical education homogenizes follow-up strategies after primary therapy for rectal cancer patients
Authors: U. Patel, K. Ode, K. S. Virgo, R. A. Audisio, W. E. Longo, F. E. Johnson
Journal: Journal of Clinical Oncology (2007)

14533 Background: The pedagogical literature suggests that continuing medical education (CME) is valuable, but objective evidence of its value has proved difficult to obtain. We investigated how self-reported surgeon age affects self-reported surveillance strategies utilized by expert surgeons following their own patients with rectal carcinoma after curative-intent treatment. We reasoned that, if there were no significant differences in strategies among surgeons of various ages, the homogenization would be ascribable to CME. Methods: We surveyed the 1,795 members of the American Society of Colon and Rectal Surgeons (ASCRS) using a questionnaire based on 4 succinct vignettes describing idealized patients treated with curative intent for TNM stages I-III rectal carcinoma. The surgeons were asked how often they use 14 specific surveillance modalities (office visit, 3 blood tests, 2 endoscopic procedures, 8 imaging studies) during years 1–5 after surgery. The motivation underlying their surveillance practices was analyzed using a menu of 12 possible factors and a Likert scale of 1 (lowest effect on motivation) to 10 (highest effect). We assessed the effect of surgeon age on follow-up intensity, controlling for TNM stage and year post- treatment, using repeated-measures ANOVA. One-way ANOVA was used to analyze the effect of surgeon age on motivation. Results: Of the 566 responses, 347 were considered evaluable. There were no significant differences among age strata (30–39, 40–49, 50–59, and = 60) in surveillance practices for any of the 4 vignettes. Only one motivating factor differed significantly among age strata: psychosocial support for the patient; surgeons = 60 were motivated more strongly (Likert score 6.9; p &lt; .05) by this factor than younger surgeons (Likert score 5.8). Conclusions: CME contributes to homogenization of this important aspect of clinical management among ASCRS surgeons. No significant financial relationships to disclose.
Renal Arteriovenous Malformation Demonstrated Angiographically in Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber Disease)
Authors: D A P Cooke
Journal: Journal of the Royal Society of Medicine (1986)

Keywords hereditary haemorrhagic telangiectasia, arteriovenous malformation, intrarenal, digital subtraction angiography
Underreporting Research Is Scientific Misconduct
Authors: lain Chalmers
Journal: JAMA (1990)

Substantial numbers of clinical trials are never reported in print, and among those that are, many are not reported in sufficient detail to enable judgments to be made about the validity of their results. Failure to publish an adequate account of a well-designed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions. Investigators, research ethics committees, funding bodies, and scientific editors all have responsibilities to reduce underreporting of clinical trials. An extended use of prospective registration of trials at inception, as well as benefiting clinical research in other ways, could help people to play their respective roles in reducing underreporting of clinical trials. (<i>JAMA</i>. 1990;263:1405-1408)
AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation
Authors: Rongfang Wei, Yan Zhu, Yuanjiao Zhang, Wene Zhao, Xichao Yu, Ling Wang, Chunyan Gu, Xiaosong Gu, Ye Yang
Journal: Cancer Communications (2022)

Abstract Background Multiple myeloma (MM) is the second most common hematological malignancy. An overwhelming majority of patients with MM progress to serious osteolytic bone disease. Aminoacyl‐tRNA synthetase‐interacting multifunctional protein 1 (AIMP1) participates in several steps during cancer development and osteoclast differentiation. This study aimed to explore its role in MM. Methods The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis. Enzyme‐linked immunosorbent assay, immunohistochemistry, and Western blotting were used to detect AIMP1 expression. Protein chip analysis, RNA‐sequencing, and chromatin immunoprecipitation and next‐generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1. The impact of AIMP1 on cellular proliferation was determined using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay in vitro and a xenograft model in vivo. Bone lesions were evaluated using tartrate‐resistant acid phosphatase staining in vitro. A NOD/SCID‐TIBIA mouse model was used to evaluate the effect of siAIMP1‐loaded exosomes on bone lesion formation in vivo. Results AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes. Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen‐activated protein kinase (MAPK) signaling pathway. Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine‐rich nuclear phosphoprotein 32 family member A (ANP32A) to regulate histone H3 acetylation. In addition, AIMP1 increased histone H3 acetylation enrichment function of GRB2‐associated and regulator of MAPK protein 2 (GAREM2) to increase the phosphorylation of extracellular‐regulated kinase 1/2 (p‐ERK1/2). Furthermore, AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1 (NFATc1) in vitro. In contrast, exosome‐coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo. Conclusions Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM, which accelerates MM malignancy via activation of the MAPK signaling pathway.
Automatic identification of tinnitus malingering based on overt and covert behavioral responses during psychoacoustic testing
Authors: Christopher J. Smalt, Jenna A. Sugai, Elouise A. Koops, Kelly N. Jahn, Kenneth E. Hancock, Daniel B. Polley
Journal: npj Digital Medicine (2022)

Tinnitus, or ringing in the ears, is a prevalent condition that imposes a substantial health and financial burden on the patient and to society. The diagnosis of tinnitus, like pain, relies on patient self-report, which can complicate the distinction between actual and fraudulent claims. Here, we combined tablet-based self-directed hearing assessments with neural network classifiers to automatically differentiate participants with tinnitus (N = 24) from a malingering cohort, who were instructed to feign an imagined tinnitus percept (N = 28). We identified clear differences between the groups, both in their overt reporting of tinnitus features, but also covert differences in their fingertip movement trajectories on the tablet surface as they performed the reporting assay. Using only 10 min of data, we achieved 81% accuracy classifying patients and malingerers (ROC AUC = 0.88) with leave-one-out cross validation. Quantitative, automated measurements of tinnitus salience could improve clinical outcome assays and more accurately determine tinnitus incidence.
Nanocarriers escaping from hyperacidified endo/lysosomes in cancer cells allow tumor-targeted intracellular delivery of antibodies to therapeutically inhibit c-MYC
Authors: Pengwen Chen, Wenqian Yang, Taehun Hong, Takuya Miyazaki, Anjaneyulu Dirisala, Kazunori Kataoka, Horacio Cabral
Journal: Biomaterials (2022)
A targetable pathway in neutrophils mitigates both arterial and venous thrombosis
Authors: Lalitha Nayak, David R. Sweet, Asha Thomas, Stephanie D. Lapping, Kenneth Kalikasingh, Annmarie Madera, Vinesh Vinayachandran, Roshan Padmanabhan, Neelakantan T. Vasudevan, Jay T. Myers, Alex Y. Huang, Alvin Schmaier, Nigel Mackman, Xudong Liao, Andrei Maiseyeu, Mukesh K. Jain
Journal: Science Translational Medicine (2022)

Arterial and venous thrombosis constitutes a major source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that arterial and venous thrombosis can occur in the same populations, suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, antithrombotic therapies targeting the immune system for therapeutics gain are lacking. Here, we show that neutrophils are key effectors of both arterial and venous thrombosis and can be targeted through immunoregulatory nanoparticles. Using antiphospholipid antibody syndrome (APS) as a model for arterial and venous thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation through genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils clustered P-selectin glycoprotein ligand 1 (PSGL-1) by cortical actin remodeling, thereby increasing adhesion potential at sites of thrombosis. Targeting clustered PSGL-1 using nanoparticles attenuated neutrophil-mediated thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutrophils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.
Atezolizumab plus Bevacizumab in Patients with Unresectable or Metastatic Mucosal Melanoma: A Multicenter, Open-Label, Single-Arm Phase II Study
Authors: Lili Mao, Meiyu Fang, Yu Chen, Xiaoting Wei, Jun Cao, Jing Lin, Peng Zhang, Ling Chen, Xiao Cao, Yujun Chen, Jun Guo, Lu Si
Journal: Clinical Cancer Research (2022)

Anti-programmed cell death-1 monotherapy is part of standard therapy for cutaneous melanoma but has low efficacy in mucosal melanoma. We evaluated the efficacy and safety of atezolizumab plus bevacizumab as first-line therapy for advanced mucosal melanoma.This multicenter, open-label, single-arm, phase II study used a Simon's two-stage design. Atezolizumab (fixed-dose, 1,200 mg) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion every 3 weeks. The primary endpoint was objective response rate (ORR), determined per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety, with adverse events (AE) summarized using NCI-CTCAE v5.0.Overall, 43 patients were enrolled, including 20 (46.5%) with unresectable and 23 (53.5%) with metastatic mucosal melanoma. Median follow-up was 13.4 months at data cutoff (July 30, 2021). Forty patients were evaluable for response: ORR was 45.0% [95% confidence interval (CI), 29.3%-61.5%; one complete response, 17 partial responses]. Median PFS was 8.2 months (95% CI, 2.7-9.6); 6- and 12-month PFS rates were 53.4% (95% CI, 36.6%-67.6%) and 28.1% (95% CI, 14.2%-43.9%), respectively. Median OS was not reached (NR; 95% CI, 14.4-NR). Six- and 12-month OS rates were 92.5% (95% CI, 78.5%-97.5%) and 76.0% (95% CI, 57.1%-87.5%), respectively. Median DOR was 12.5 months (95% CI, 5.5-NR). Overall, 90.7% (39/43) of patients experienced treatment-related AEs; 25.6% (11/43) experienced grade ≥3 events.Atezolizumab in combination with bevacizumab showed promising efficacy and manageable safety in patients with advanced mucosal melanoma.
Facts and Hopes in Cancer Antigens Recognized by T Cells
Authors: Walther Brochier, Orian Bricard, Pierre G. Coulie
Journal: Clinical Cancer Research (2022)

Abstract T cells are key effectors of our immune response against tumors and exert their antitumor effects upon recognizing a variety of tumor-specific peptides presented by HLA molecules on the surface of tumor cells. The identification of the tumor-specific antigens of a given tumor is not required for immune checkpoint therapy (ICT), which mainly reactivates existing tumor-specific T cells together with T cells of unknown specificities. To decrease the activation of non–tumor-specific T cells, active or passive immunizations against tumor-specific antigens are considered. These immunizations require the identification of at least some of the tumor-specific antigens displayed on the tumor cells of a patient. While this has become an easy task for tumors with a large number of mutations generating neoantigens, it remains difficult for the remainder. Here, we review some facts about human tumor-specific or tumor-associated antigens, as well as some hopes for their future use in cancer immunotherapy.
To Rb or Not to Rb: Uncovering Unique Subsets of Small Cell Lung Carcinoma
Authors: Navin R. Mahadevan, Lynette M. Sholl
Journal: Clinical Cancer Research (2022)

Summary The use of IHC as a surrogate for specific underlying genomic alterations has allowed for increasingly comprehensive and accurate diagnosis of small cell lung carcinoma (SCLC). This is especially relevant in light of the increasing recognition of the biologic heterogeneity of this aggressive and difficult-to-treat lung tumor. Integrated genomic and IHC profiling of Rb status in SCLC yields new diagnostic insights and has translational implications. See related article by Febres-Aldana et al., p. 4702
Bioinformatically Expanded Next-Generation Sequencing Analysis Optimizes Identification of Therapeutically Relevant <i>MET</i> Copy Number Alterations in &amp;gt;50,000 Tumors
Authors: James P. Solomon, Soo-Ryum Yang, Noura J. Choudhury, Ryan N. Ptashkin, Nasrin Eslamdoost, Christina J. Falcon, Axel Martin, Andrew Plodkowski, Clare Wilhelm, Ronglai Shen, Marc Ladanyi, Michael Berger, Yanming Zhang, Alexander Drilon, Maria E. Arcila
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Clinical relevance thresholds and laboratory methods are poorly defined for MET amplification, a targetable biomarker across malignancies. Experimental Design: The utility of next-generation sequencing (NGS) in assessing MET copy number alterations was determined in &amp;gt;50,000 solid tumors. Using fluorescence in situ hybridization as reference, we validated and optimized NGS analysis. Results: Incorporating read-depth and focality analyses achieved 91% concordance, 97% sensitivity, and 89% specificity. Tumor heterogeneity, neoplastic cell proportions, and genomic focality affected MET amplification assessment. NGS methodology showed superiority in capturing overall amplification status in heterogeneous tumors and defining amplification focality among other genomic alterations. MET copy gains and amplifications were found in 408 samples across 23 malignancies. Total MET copy number inversely correlated with amplified segment size. High-level/focal amplification was enriched in certain genomic subgroups and associated with targeted therapy response. Conclusions: Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.